Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein RamC is required for the production of the spore-forming cells called aerial hyphae by the filamentous bacterium Streptomyces coelicolor. We showed that RamC, which contains several weakly predicted membrane-spanning sequences, is located exclusively in the S. coelicolor membrane. By constructing site-directed mutants in the cloned ramC gene and complementing a ramC null mutant, we showed that protein kinase-like sequence motifs in the amino-terminal half of the protein are required for function in vivo. These data suggest that RamC is a membrane-associated receptor kinase.
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PMID:Membrane association and kinase-like motifs of the RamC protein of Streptomyces coelicolor. 1216 18

Neutral antagonists and inverse agonists can produce different cellular responses in some systems. The effects of chronic (14-day) infusion of three ligands, ICI-118,551, carvedilol, and alprenolol were examined in cardiac tissue from wild-type and transgenic mice with cardiac-specific overexpression of the human beta2-adrenoceptor. These ligands vary in their negative efficacy at the human beta2-adrenoceptor, with two (ICI-118,551 and carvedilol) behaving as inverse agonists and one (alprenolol) behaving as a neutral antagonist. Cardiac tissue from the transgenic mice exhibited elevated levels of protein kinase A activity and G protein receptor kinase-2. Fourteen-day infusions of the three ligands lowered the elevated levels of protein kinase A activity of the transgenic hearts to control levels. Alprenolol and carvedilol also decreased G protein receptor kinase-2 amounts to control levels. The left atria from transgenic mice exhibited an impaired inotropic response to histamine relative to responses of wild-type mice atria. Infusions of the inverse agonists and a neutral antagonist at the beta2-adrenoceptor significantly restored the impaired histamine response. Restoration of protein kinase A activity and the impaired histamine responses in the atria from transgenic mice can be observed following 14-day infusions of both a neutral antagonist and inverse agonists. The reversal of the effects of the transgene by both inverse agonists and a neutral antagonist suggests that agonist occupancy, and not spontaneous activity, of the beta2-adrenoceptor is producing the elevated protein kinase A activity and the impaired histamine response.
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PMID:Chronic infusion of beta-adrenoceptor antagonist and inverse agonists decreases elevated protein kinase A activity in transgenic mice with cardiac-specific overexpression of human beta 2-adrenoceptor. 1219 31

Proliferation of legume nodule primordia is controlled by shoot-root signaling known as autoregulation of nodulation (AON). Mutants defective in AON show supernodulation and increased numbers of lateral roots. Here, we demonstrate that AON in soybean is controlled by the receptor-like protein kinase GmNARK (Glycine max nodule autoregulation receptor kinase), similar to Arabidopsis CLAVATA1 (CLV1). Whereas CLV1 functions in a protein complex controlling stem cell proliferation by short-distance signaling in shoot apices, GmNARK expression in the leaf has a major role in long-distance communication with nodule and lateral root primordia.
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PMID:Long-distance signaling in nodulation directed by a CLAVATA1-like receptor kinase. 1241 74

The inhibition of angiogenesis through vascular endothelial growth factor (VEGF) receptor targeting is a strategy that is relatively tumour selective. The high selectivity achieved with neutralising antibodies, soluble receptors and ribozymes reduces the risk of adverse reactions not related to VEGF inhibition itself. Small-molecule, orally-active protein kinase inhibitors provide an attractive alternative for chronic therapy, although specifically targeting a small subset of protein kinases from the approximately 550 expressed in mammalian cells is a challenge. Current efforts have resulted in promising clinical data for several synthetic VEGF receptor kinase inhibitors, of which PTK787/ZK222584 and ZD6474 are proceeding into large size clinical trials. It seems likely that blockers of the VEGF signalling pathway will be unsuitable for monotherapy, and that their role will be as an adjunct to additional antiangiogenic agents together with directly-acting antitumour agents or radiation therapy. Caution is needed with combinations of anti-VEGF therapies and cytotoxic agents, as coadministration of cytotoxic agents with either the kinase inhibitor SU5416 or the VEGF antibody avastin appears to be associated with bleeding and thrombotic adverse events.
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PMID:Therapies directed at vascular endothelial growth factor. 1245 33

Carney complex (CNC) is caused by PRKAR1A-inactivating mutations. PRKAR1A encodes the regulatory subunit type I-alpha (RIalpha) of the cAMP-dependent kinase (PKA) holoenzyme; how RIalpha insufficiency leads to tumorigenesis remains unclear. In many cells PKA inhibits the extracellular receptor kinase (ERK1/2) cascade of the mitogen-activated protein kinase (MAPK) pathway leading to inhibition of cell proliferation. We investigated whether the PKA-mediated inhibitory effect on ERK1/2 is affected in CNC cells that carry germline PRKAR1A mutations. PKA activity both at baseline and after stimulation with cAMP was augmented in cells carrying mutations. Quantitative message analysis showed that the main PKA subunits expressed were type I (RIalpha and RIbeta) but RIalpha was decreased in mutant cells. Immunoblot assays of ERK1/2 phosphorylation by the cell- and pathway-specific stimulant lysophosphatidic acid (LPA) showed activation of this pathway in a time- and concentration-dependent manner that was prevented by a specific inhibitor. There was a greater rate of growth in mutant cells; forskolin and isoproterenol inhibited LPA-induced ERK1/2 phosphorylation in normal but not in mutant cells. Forskolin inhibited LPA-induced cell proliferation and metabolism in normal cells, but stimulated these parameters in mutant cells. These data were also replicated in a pituitary tumor cell line carrying the most common PRKAR1A mutation (c.578del TG), and an in vitro construct of mutant PRKAR1A that was recently shown to lead to augmented PKA-mediated phosphorylation. We conclude that PKA activity in CNC cells is increased and that its stimulation by forskolin or isoproterenol increases LPA-induced ERK1/2 phosphorylation, cell metabolism and proliferation. Reversal of PKA-mediated inhibition of this MAPK pathway in CNC cells may contribute to tumorigenesis in this condition.
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PMID:Protein kinase-A activity in PRKAR1A-mutant cells, and regulation of mitogen-activated protein kinases ERK1/2. 1281 76

D hordein, a prolamin storage protein of barley endosperms, is highly homologous to the high molecular weight (HWM) glutenin subunits, which are the major determinants of bread-making quality in wheat flour. In hexaploid wheat (AABBDD), each genome contains two paralogous copies of HMW-glutenin genes that encode the x- and y-type HMW-glutenin subunits. Previously, we reported the sequence analysis of a 102-kb genomic region that contains the HMW-glutenin locus of the D genome from Aegilops tauschii, the donor of the D genome of hexaploid wheat. Here, we present the sequence analysis of a 120-kb D-hordein region of the barley genome, a more distantly related member of the Triticeae grass tribe. Comparative sequence analysis revealed that gene content and order are generally conserved. Genes included in both of these orthologous regions are arranged in the following order: a Xa21-like receptor kinase, an endosperm globulin, an HMW prolamin, and a serine (threonine) protein kinase. However, in the wheat D genome, a region containing both the globulin and HMW-glutenin gene was duplicated, indicating that this duplication event occurred after the separation of the wheat and barley genomes. The intergenic regions are divergent with regard to the sequence and structural organization. It was found that different types of retroelements are responsible for the intergenic structure divergence in the wheat and barley genomes. In the barley region, we identified 16 long terminal repeat (LTR) retrotransposons in three distinct nested clusters. These retroelements account for 63% of the contig sequence. In addition, barley D hordein was compared with wheat HMW glutenins in terms of cysteine residue conservation and repeat domain organization.
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PMID:Structural organization of the barley D-hordein locus in comparison with its orthologous regions of wheat genomes. 1466 27

Perception of the plant steroid hormone brassinolide (BL) by the membrane-associated receptor kinase BRI1 triggers the dephosphorylation and accumulation in the nucleus of the transcriptional modulators BES1 and BZR1. We identified bsu1-1D as a dominant suppressor of bri1 in A abidopsis. BSU1 encodes a nuclear-localized serine-threonine protein phosphatase with an N-terminal Kelch-repeat domain, and is preferentially expressed in elongating cells. BSU1 is able to modulate the phosphorylation state of BES1, counter acting the action of the glycogen synthase kinase-3 BIN2, and leading to inc eased steady-state levels of dephosphorylated BES1. BSU1 belongs to a small gene family; loss-of-function analyses unravel the extent of functional overlap among members of the family and confirm the role of these phosphatases in the control of cell elongation by BL. Our data indicate that BES1 is subject to antagonistic phosphorylation and dephosphorylation reactions in the nucleus, which fine-tune the amplitude of the response to BL.
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PMID:Nuclear protein phosphatases with Kelch-repeat domains modulate the response to brassinosteroids in Arabidopsis. 1497 18

Self-incompatibility (SI) response in Brassica is initiated by haplotype-specific interactions between the pollen-borne ligand S locus protein 11/SCR and its stigmatic S receptor kinase, SRK. This binding induces autophosphorylation of SRK, which is then thought to trigger a signaling cascade that leads to self-pollen rejection. A recessive mutation of the modifier (m) gene eliminates the SI response in stigma. Positional cloning of M has revealed that it encodes a membrane-anchored cytoplasmic serine/threonine protein kinase, designated M locus protein kinase (MLPK). Transient expression of MLPK restores the ability of mm papilla cells to reject self-pollen, suggesting that MLPK is a positive mediator of Brassica SI signaling.
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PMID:A membrane-anchored protein kinase involved in Brassica self-incompatibility signaling. 1500 63

Initial studies with angiogenesis inhibitors showed little clinical benefit. However, recently reported clinical studies in colorectal cancer have shown that bevacizumab, a vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with cytotoxic therapy has positive effects on patient survival. Furthermore, the VEGF receptor kinase (VEGF-R) tyrosine kinase inhibitor, vatalanib, has also shown encouraging results in colorectal cancer, with molecular resonance imaging providing evidence that the anti-tumor efficacy was indeed the result of anti-angiogenic activity. Both of these agents are progressing in phase III trials. This proof of concept has stimulated the desire for second-generation VEGF-R inhibitors having an improved profile. Structural biology insight regarding the binding mode of protein kinase inhibitors is valuable for the design of molecules possessing superior selectivity, efficacy and tolerability. Towards this goal, we have developed a new series of VEGF-R2 kinase inhibitors, based upon an anthranilic acid amide scaffold. An X-ray crystal structure of a representative compound, AAL993 (ZK260253), in complex with the catalytic domain of diphosphorylated VEGF-R2 has revealed that this molecule binds to an inactive conformation of the protein. This binding mode, similar to that observed for the anti-leukemia drug, imatinib in complex with c-Abl kinase, may be responsible for the high selectivity of AAL993 and provides valuable insight for the design of further compounds.
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PMID:Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis. 1502 47

The relationship between myocardial G protein receptor kinase (GRK) expression and beta-adrenoceptor signalling in human left heart diseases has not been fully elucidated yet. In this study, we characterized and compared the GRK2-7 expression in patients with left ventricular volume overload disorders and dilated cardiomyopathic hearts, and evaluated the relationship of this expression with alterations in myocardial beta-adrenoceptor signalling in volume overload, in order to test the notion that GRK functional expression is influenced in a disease-specific and selective fashion. We established that GRK2, GRK3, and GRK5 are well expressed, while GRK4, GRK6, and GRK7 are only scarcely detectable in the healthy human heart. Compared to control hearts (n=8), GRK2 mRNA expression was elevated by 71% (P<0.005) in the left ventricle, 110% (P<0.05) in the right ventricle, 130% (P<0.05) in the left atrium, and 1300% (P<0.005) in the right atrium (RA) of the dilated cardiomyopathy hearts (n=6). In the volume overload group (n=10), it was increased by approximately 40% (P<0.05) in the left ventricle, 38% in the right ventricle, 81% (P<0.05) in the left atrium, and 850% (P<0.005) in the right atrium. On the other hand, GRK5 was significantly elevated only in the left ventricle by 68% (P<0.05) in the dilated cardiomyopathy hearts and by 48% (P<0.01) in volume overload patients, while in contrast, GRK3 remained unchanged in dilated cardiomyopathy, but was slightly elevated by 36% (P=0.05) in the right ventricle of the volume overload patients. The alterations in GRK expression were accompanied with a decrease in myocardial beta(1)-adrenoceptor mRNA in all four chambers, and these trends in gene expression were paralleled with those of their immunodetectable protein levels. Furthermore, these changes were in association with a decrease in downstream receptor-stimulated, adenylyl cyclase-mediated functional expression and an increase in ventricular protein kinase A activity. The results point to differences in which myocardial GRKs are regulated in cardiac disease, whereby changes in GRK2 expression may be related to the global effects of the disease on myocardial adrenoceptor function and those in GRK5 may be localized to the ventricles, depending on the nature of the myocardial load.
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PMID:Differential functional expression of human myocardial G protein receptor kinases in left ventricular cardiac diseases. 1508 39


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